Liver disease caused by viral hepatitis is now a leading cause of death in HIV-infected persons, mostly due to chronic viral hepatitis. This proposal is conceived to identify molecular targets in HIV-HCV co-infected persons at risk for progressive liver disease that can be exploited therapeutically. There are at least two highly plausible mechanisms through which HIV could promote liver fibrosis in a person with ongoing chronic viral hepatitis that focus on the hepatic macrophage (Kupffer cell). There are preliminary data that show that HIV infects Kupffer cells, the largest reservoir of resident tissue macrophages in the body. While the extent and ultimate consequence of HIV infection of these cells is unknown, the Kupffer cell's role governing inflammation/fibrosis via altered signaling pathways provides a pathogenic link. In addition, HIV infection of intestinal tissues has recently been shown to markedly enhance the translocation of bacterial products (e.g. lipopolysaccharide) through portal circulation to the liver. Since Kupffer cells are chiefly responsible for the clearance of these products and since experimentally induced microbial translocation enhances liver fibrosis, HIV also could promote liver fibrosis via Kupffer cells through this mechanism. The goal of this investigation is to extend these observations by focusing on the effect of HIV infection and HIV-related microbial translocation on Kupffer cells. Initial investigations will utilize stored liver biopsies from a well-characterized repository of HIV-infected persons, focusing on defining the extent of HIV infection of Kupffer cells using immunohistologic and molecular methods. Since CCR5, a known coreceptor mediating HIV infection, plays a role in the development of experimental liver disease, subsequent studies will use isolated human Kupffer cells to identify key chemokine coreceptors on Kupffer cells that permit HIV infection. Finally, the ex vivo Kupffer cell model will be further developed to study fibrogenic signaling patterns, i.e. TGF-beta and TNF-alpha, upon lipopolysaccharide induction and HIV infection. The proposed studies will define essential mechanisms of liver disease in HIV-HCV co-infection, and the investigators will develop insights into novel therapeutics for co-infected persons.